Neuroradiology (2003) 45: 345–351 DOI 10.1007/s00234-003-0959-3

Y. Liu J.O. Karonen R.L. Vanninen J. Nuutinen J. Perkio¨ P.A. Vainio S. Soimakallio H.J. Aronen

Received: 16 November 2002 Accepted: 28 January 2003 Published online: 16 May 2003
Springer-Verlag 2003

Y. Liu (&) Æ J.O. Karonen R.L. Vanninen Æ P.A. Vainio S. Soimakallio Æ H.J. Aronen Department of Clinical Radiology, Kuopio University Hospital, P.O. Box 1777, 70211 Kuopio, Finland E-mail: yawu.liu@kuh.fi Tel.: +358-17-173324 Fax: +358-17-173341 J.O. Karonen Department of Radiology, Mikkeli Central Hospital, Mikkeli, Finland J. Nuutinen Department of Neurology, Kuopio University Hospital, Kuopio, Finland J. Perkio¨ Æ H.J. Aronen Department of Radiology, Helsinki University Central Hospital, Finland J. Perkio¨ Department of Physical Sciences, University of Helsinki, Finland J. Perkio¨ Æ H. Aronen Functional Brain Imaging Unit, Helsinki Brain Research Centre, Finland

DIAGNOSTIC NEURORADIOLOGY

Detecting the subregion proceeding to infarction in hypoperfused cerebral tissue: a study with diffusion and perfusion weighted MRI

Abstract Diffusion and perfusion weighted MRI have been widely used in ischaemic stroke. We studied 17 patients in whom ischaemic areas showed an ischaemic core, an area of infarct growth and hypoperfused but ultimately surviving tissue. Apparent diffusion coefficients (ADC) were measured on days 1, 2, and 8 in the three subregions and in contralateral control areas. Cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) were measured in these regions on day 1 perfusion maps. On day 1, the ischaemic core had very low ADC and CBF and increased MTT. The ADC in the ischaemic core gradually increased during the week. The area of infarct growth on day 1 had slightly but significantly decreased ADC (96% of control, P=0.028), moderately decreased CBF and increased MTT. On day 1 the hypoperfused but surviving tissue had slightly but significantly increased ADC (103% of control, P=0.001), mildly decreased CBF and increased CBV and MTT. The ADC of the area of infarct growth decreased to the same level as in the ischaemic core on days 2 and 8. That

Introduction Diffusion-weighted MRI (DWI) is sensitive to translational movement of water and can be used for measuring

of surviving tissue was still above normal on day 2 (103% of control), but had returned to the normal level by day 8. Measurement of ADC combined with perfusion MRI may help distinguish different subregions in acutely hypoperfused brain. Keywords Stroke Æ Ischaemic penumbra Æ Magnetic resonance imaging Æ Diffusion Æ Perfusion

diffusion of water in vivo. In ischaemic brain, diffusion of water is decreased and this can be detected very early after the onset of ischaemia using DWI [1]. The apparent diffusion coefficient (ADC) calculated from DWI raw

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data gives quantitative information on diffusion. Animal stroke models have shown that the reduction in ADC in an ischaemic lesion correlates with the reduction of cerebral blood flow (CBF) and the disturbance of energy metabolism [2]. Thus, changes in ADC with time reflect the pathological status of the ischaemic lesions during cerebral infarction [3, 4], while perfusion-weighted MRI (PWI) shows the area which is hypoperfused compared to normal brain [5, 6]. Combined DWI and PWI provide qualitative and quantitative information on cerebral ischaemia [7, 8, 9, 10, 11]. At present, the effective therapeutic window for ischaemic stroke is limited to 6 h after the onset of symptoms, the hyperacute stage. Recent work has shown that DWI and PWI can be used to characterise the hypoperfused tissue proceeding to infarction and that which will survive [11, 12, 13, 14]. However, only a minority of patients with ischaemic stroke are admitted within 6 h of the onset of symptoms. There is evidence that many patients have potentially salvageable tissue even up to 24 hours after onset. Some of these might benefit from novel therapies. Clinical decision-making is likely to benefit from better understanding of the characteristics of different subregions in acutely hypoperfused tissue. Our purposes were to clarify whether it is possible in the acute stage to distinguish between hypoperfused tissue which will survive and that which will proceed to infarction, by looking at ADC and haemodynamic parameters, and to investigate the temporal changes in ADC in the different subregions during the first week of ischaemic stroke.

Materials and methods We selected 17 patients from a consecutive series of 57 with acute ischaemic stroke who underwent DWI and PWI as a part of our acute stroke imaging project. The ten men and seven women were retrospectively selected according to the following criteria: they had suffered their first-ever ischaemic stroke in the anterior cerebral circulation; they successfully underwent DWI and PWI on the first day (day 1), on day 2 and 1 week after the onset of symptoms (day 8); and the infarct core and an area of infarct growth or surviving tissue, which had a prolonged mean transit time (MTT) on day 1 but which did not proceed to infarction on day 8, seen on DWI and PWI. No patient received thrombolysis or experimental neuroprotection therapies. We excluded patients with lacunar, posterior cerebral artery territory, bilateral or old cerebellar infarcts, those who did not have a follow-up examination on day 8 and those in whom analysis was unsatisfactory or in whom there were technical failures. The mean age of the patients was 70±8 years. On admission, their median National Institutes of Health Stroke Scale (NIHSS) score was 15 (range 4–30). The median time from the onset of symptoms to the first MRI was 8 h, range 3.5– 23 h. The onset of symptoms was defined as the time the patient was last known to be without symptoms. We obtained informed consent from the patient or assent from a relative. The study design was approved by the ethics committee of our institution.

All MRI was performed at 1.5 tesla on an echoplanar-capable imager using a head coil. Each imaging study consisted of DWI, PWI and conventional MRI. This report is based on days 1, 2, and 8 DWI and day 1 PWI. DWI was performed with a single-shot echoplanar spin-echo sequence (TR 4000 TE 103 ms); the other parameters were slice thickness 5 mm, interslice gap 1.5 mm, field of view (FOV) 260 mm, matrix 96·128 interpolated to 256·256 and acquisition time 20 s. We obtained 19 axial slices angled to the orbitomeatal line: a T2-weighted image without diffusion weighting (b 0 s/mm2) and three diffusion-weighted images with orthogonally applied diffusion gradients (b 1000 s/mm2). In order to avoid the effects of diffusion anisotropy, isotropic diffusion-weighted images were calculated on a pixel-by-pixel basis as the average of all three diffusion-weighted images. The trace ADC maps were computed   using the  equation ADCi;j ¼ ln Si;j ð0Þ
ln Si;jav ð1000Þ ð1Þ where the subscript i, j denotes the image voxel; Si,j(0) is the image intensity at b=0; Si,jav(1000) the directionally averaged signal intensity at b=1000. An echoplanar spin-echo sequence was used for PWI (TR 1500 TE 78 ms, FOV 260 mm, matrix 116·256). We imaged seven 5 mm thick slices with 1.5 mm interslice gap at the slice positions containing the largest lesions on DWI, acquiring 40 images per slice at intervals of 1.5 s. We injected 0.2 mmol/kg gadopentetate dimeglumine into an antecubital vein at 5 ml/s, followed by a 15 ml bolus of saline, using a power injector, after four baseline measurements. Perfusion raw images were postprocessed to generate maps of cerebral blood volume (CBV), CBF and MTT [6, 15]. The shape of the arterial input function was determined from voxels on a branch of the normal middle cerebral artery contralateral to the ischaemic lesion, showing large signal losses during the bolus passage. The infarct volumes on days 1, 2, and 8 were measured from both the 19 isotropic DWI and the seven isotropic images which matched with slice positions of PWI on day 1. The volume of the abnormality on the MTT map on day 1 was also measured. The volumes were calculated by drawing regions of interest (ROI) along the lesion margins on the isotropic DWI and MTT maps and then multiplying the area by the slice thickness. When measuring infarct volumes on isotropic DWI, the trace ADC maps were reviewed, to allow for a possible contribution of T2 shine-through to the signal intensity. The interslice gap was estimated to contain a lesion of the same size as the slice above it, and the lesion in the gap was included in the volume calculation. By reviewing the serial image, the ischaemic core, the area of infarct growth and the surviving tissue were identified in the seven slices of each patient [12, 13, 16]. The ischaemic core was defined as the region giving high signal on isotropic DWI on day 1. Recent studies have shown that the DWI lesion or decreased ADC may be reversible after extremely early reperfusion [17, 18], but there are few observations of recovery of ischaemic brain tissue with decreased diffusion after the first 6 h in humans. Histological study suggests that permanent resolution of a lesion on DWI does not necessarily indicate complete salvage of brain tissue from ischaemic injury [19]. We therefore defined the infarcted tissue as that giving high signal on DWI, so that we defined the area of infarct growth as the difference between high-signal regions on isotropic DWI on days 1 and 8. The surviving tissue was defined as that which had a prolonged MTT on day 1 but which had not proceeded to infarction on day 8. Fig. 1 illustrates how the ischaemic regions were defined. Irregular ROI were drawn on the ischaemic core, the area of infarct growth, and the surviving tissue on isotropic DWI, including both grey and white matter, then copied onto the trace ADC maps. In order to avoid the effect of cerebrospinal fluid (CSF), the ROI were adjusted to exclude sulci and brain adjacent to CSF with blurred margins. Control ROI of similar size and

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Table 1 The relative cerebral blood volume (relCBV), cerebral blood flow (relCBF) and mean transit time (relMTT) (means±SD) in the ischaemic subregions on the first day of stroke Parameter

22±9%a 36±12%a 179±42%

relCBF relCBV relMTT a

Ischaemic core (n=17)

Area of infarct growth (n=11)

Surviving tissue (n=17)

47±20%a 80±14%a 181±41%

66±13%a 110±18%a 176±34%

Significant difference (P<0.05) between each region

The mean ADC and relative haemodynamic parameters of each zone in each patient proved to be normally distributed by the Kolmogorov-Smirnov test. A paired Student’s t-test was used to compare the variables on the two sides. One-way ANOVA with Tukey post hoc multiple comparisons was used to compare the variables among subregions. The correlation between the mean relADC and mean relCBF and relCBV in each patient were studied using Pearson’s correlation coefficient. A two-tailed value of P<0.05 was accepted as significant.

Results

Fig. 1A–D Ischaemic subregions. An infarct enlarged significantly on isotropic diffusion-weighted images between A day 1 and B day 8. C On a map of mean transit time, the area of hypoperfusion is seen in the right hemisphere with relatively clear margins. D The black area represents the ischaemic core, the grey area the area of infarct growth and the white area the hypoperfused but ultimately surviving tissue site were drawn on the contralateral hemisphere. The ROI were copied to the corresponding regions on day 1 PWI maps. Since we cannot measure absolute values for perfusion, relative CBF (relCBF), CBV (relCBV), and MTT (relMTT) were calculated as ratios of the values on the ischaemic side and the other side. We also calculated relative ADC (relADC) to study the relationship of ADC to relCBF and relCBV, and to normalise intersubject variation. The mean value for each zone in each patient was calculated by averaging all individual measurements on different slices with weighting of the size of each ROI. A total of 76, 66, and 104 ROI were drawn in the ischaemic core, the area of infarct growth and the surviving tissue, respectively. The size of the ROI was 0.04–2.42 cm3.

The ischaemic core, the area of infarct growth, and the surviving tissue could be identified in 11 of 17 patients. The ischaemic core and the surviving tissue were detected in the remaining patients. The mean total infarct volume measured from 19 isotropic DWI slices was 56±51 cm3on day 1, 91±67 cm3 on day 2 and 118±86 cm3 on day 8; in the seven slices it was 45±41 cm3, 71±51 cm3 and 90 ± 56 cm3, respectively. The mean volume of abnormality on MTT maps in the seven slices on day 1 was 196±64 cm3. The relative CBF, CBV, and MTT in the ischaemic subregions are summarised in Table 1, the mean ADC in the ischaemic and contralateral areas in Table 2. The changes in ADC over time in the ischaemic subregions are presented in Fig. 2. On day 1, the relCBF, relCBV and relMTT in the ischaemic core or surviving tissue were not statistically significant different (P‡0.067) between 11 patients with infarct growth and six without. The ADC in the ischaemic core and surviving tissue in the patients with infarct growth did not differ significantly from those of patients without on days 1, 2, and 8 (P‡0.223).

Table 2 Apparent diffusion coefficients (10-3mm2/s; means±SD) in the ischaemic subregions and their contralateral control areas on days 1, 2 and 8 after the onset of symptoms Day

1 2 8 a

Ischaemic core (n=17)

Area of infarct growth (n=11)

Surviving tissue (n=17)

Ischaemic

Contralateral

Ischaemic

Contralateral

Ischaemic

Contralateral

0.41±0.04a 0.43±0.09a 0.66±0.18

0.76±0.05 0.77±0.05 0.75±0.03

0.74±0.06a 0.40±0.05a 0.60±0.12a

0.78±0.05 0.77±0.03 0.76±0.04

0.81±0.04a 0.79±0.04a 0.77±0.05

0.78±0.04 0.77±0.03 0.77±0.04

Significant difference (P <0.05) between ischaemic and contralateral hemisphere

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b

Fig. 2A–C Time-course of apparent diffusion coefficients (ADC). A In the ischaemic core, the ADC gradually increased. B In the area of infarct growth, it was significantly decreased (P=0.028) on day 1 but increased to the same level as in the ischaemic core on days 2 and 8. C In the surviving tissue ADC was elevated on days 1 (P=0.001) and 2 (P=0.007), but returned to normal on day 8. Bars indicate the 95% confidence interval of the means

ADC gradually increased during the first week. The area of infarct growth showed slightly but significantly decreased ADC (96% of control, P=0.028), moderately decreased CBF (47% of control, P<0.001) and CBV (80% of control, P=0.001), and increased MTT (181% of control, P<0.001). The surviving tissue had slightly but significantly increased ADC (103% of control, P=0.001), mildly decreased CBF (66% of control, P<0.001), and increased CBV (110% of control, P=0.040) and MTT (176% of control, P<0.001). The ADC of the area of infarct growth decreased to the level of that in the ischaemic core on days 2 and 8 (P=0.339 and 0.406, respectively). The ADC of the surviving tissue was still increased on day 2 (103% of control, P=0.007), but had returned to the normal level on day 8 (P=0.497) (Fig. 2). On day 1, the mean relADC in the three ischaemic subregions correlated significantly with relCBF (r=0.819, P<0.001), and relCBV (r=0.901, P<0.001).

Discussion

The ischaemic core had very low ADC (54% of control, P<0.001) and CBF (22% of control, P<0.001) and increased MTT (179% of control, P<0.001), and the

Subregions of ischaemic tissue have been characterised by haemodynamic parameters in human studies [12, 13, 14, 16, 20, 21, 22, 23, 24]. It is well documented that the ischaemic tissue with very low CBF (<10–12 ml/ 100 g/min) will rapidly proceed to irreversible damage [22, 25]. In the surrounding region of moderately ischaemic tissue (CBF approximately 10–20 ml/100 g/ min), the tissue will gradually undergo infarction if low flow persists [20, 22]. If CBF is >20 ml/100 g/min, the tissue will be likely to escape infarction [20]. In our study, the ischaemic core, the area of infarct growth and the surviving tissue revealed significant differences in both relCBF and relCBV. In a single-photon computed emission tomography (SPECT)/MRI study [16], the relCBF measured from PWI in the ischaemic core and the area of infarct growth were 13% and 35%, respectively. Our CBF values were slightly higher in the ischaemic core and the area of infarct growth (22% and 47%, respectively). In the previous study, the ROI covered the cortex to compare the findings on SPECT and PWI. Therefore, mainly grey matter and only small parts of subcortical white matter were covered. Our ROI covered not only grey matter and subcortical white matter, but also a considerable amount of deep white matter. Normal grey and white matter have quite different CBF, and the arteries and arterioles in the

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sulci have an effect on perfusion as measured by PWI [26]. We excluded the sulci and grey matter with blurry margins to avoid the effects of CSF. These differences are likely to account for the discrepancy between these two studies. In quantitative studies with humans, normal subjects aged more than 50 years have CBF of about 50 ml/ 100 g/min for grey and 20 ml/100 g/min for white matter [27, 28]. Therefore, the CBF of mixed grey and white matter is approximately 35 ml/100 g/min in normal elderly subjects. If we use this figure, the relCBF of the ischaemic core, the area of infarct growth and the surviving tissue can be converted to 8, 16 and 23 ml/100 g/ min, respectively. These values are in good agreement with the CBF derived from positron-emission tomography studies [20, 21, 22]. We showed that in the acute stage both CBF and CBV correlate with ADC, suggesting that cell function depends on residual blood flow [29, 30, 31], autoregulatory vasodilatation and collateral circulation [32]. Autoregulatory vasodilatation and collateral circulation seem to play an important role in maintaining the viability of ischaemic tissue [32]. It has been shown [33, 34] that the ADC varies in the ranges 0.68–1.09·10-3 mm2/s 0.62–0.88·10-3 mm2/s between different regions of grey and white matter, respectively. It depends on the relative amounts of grey and white matter in the ROI. Therefore, it is difficult to define any absolute, universally applicable value for change in ADC in an ROI-based measurement. However, since the brain is symmetrical, comparison between the ADC on the ischaemic and the other side enables assessment of even slight changes in ADC in the ischaemic tissue. The ADC of the area of infarct growth was slightly but significantly lower than on the control side. In contrast, the ADC of surviving tissue was slightly but significantly higher during the acute stage. Thus, determination of the ADC may be useful in predicting the outcome for ischaemic tissue. Pierpaoli et al. [3] found that during the acute stage, in the tissue with normal cellular ultrastructure adjacent to the infarcted tissue, the ADC can rise, due to the swelling of the perivascular astrocytic processes typical of vasogenic oedema. Our finding of increased ADC in the surviving tissue on days 1 and 2 was probably attributable to mild vasogenic oedema. Another possible explanation for the decrease in ADC in the area of infarct growth and the increase in the surviving tissue might be tissue perfusion. When using values of b less than approximately 300 s/mm2 the results are contami-

nated by capillary intravoxel incoherent motion (IVIM) [35, 36]. With b less than approximately 900 s/mm2, Turner et al. [37] found that up to 14% of the IVIM signal was contributed by random perfusion of fluid in normal cerebral cortex. Although we used a higher diffusion gradient (1000 s/mm2), making ADC less sensitive to perfusion, the contribution of capillary IVIM on ADC measurement needs to be considered. In the area of infarct growth, the CBF and CBV were significantly lower than the control values, loss of capillary IVIM might therefore also contribute to the relative reduction in ADC. On the other hand, in the surviving tissue, as the CBV was significantly increased, the volume proportion of capillaries in voxels was consequently increased, enhancing the perfusion contribution to ADC in the surviving tissue. In a rat stroke model [38], the ADC in the ischaemia-nonischaemia transitive region was higher than in the normal region and those with severe ischaemia. This supports our finding of increased ADC in the surviving tissue on days 1 and 2. The ADC of surviving tissue had returned to normal on day 8. This may be due to collateral circulation and/or recanalisation permitting the nutrient supply to return to adequate levels [39]. Ischaemia is detected more readily on ADC maps than on diffusion-weighted images in detecting ischaemia; a slight reduction of ADC cannot be detected visually on DWI [19, 23]. Schlaug et al. [23] reported an 8% reduction in ADC in the area of infarct growth in humans, which could not been seen on day 1 DWI. A pathological study showed that selective necrosis of less than 4%–28% of neurones could reduce ADC, but did not cause visually detectable signal abnormalities on DWI or T2-weighted images [19]. Recent studies [12, 40] showed that within 6 hours of the onset, the ADC was lower in the area of infarct growth than in the oligaemic tissue. Our results support this, but in the previous studies, the ADC of the oligaemic tissue was not different from that of the contralateral hemisphere. We found the ADC of the surviving tissue to be slightly higher than that of the opposite side. We speculate that, in addition to the difference in definition of the surviving tissue, the longer time from ictus to imaging may be the main reason for this difference. Acknowledgements This work was supported by Kuopio University Hospital (EVO funding 307/97 and 21/98), the Radiological Society of Finland, the Academy of Finland, the Sigrid Juse´lius Foundation, the Instrumentarium Science Foundation, Biomedicum Helsinki Foundation, the Aarne Koskelo Foundation, the Paulo Foundation, and the Paavo Nurmi Foundation.

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